3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans

MDMA (Ecstasy) produces a mix of stimulant and psychedelic effects mediated by brain monoamines, especially serotonin and dopamine. It also shows toxic activity toward brain serotonin neurons in animals, including non-human primates, at doses close to those used by humans. Whether MDMA is neurotoxic in humans remains under investigation, but documented adverse effects include systemic complications and neuropsychiatric consequences involving mood, cognition, and anxiety. Because MDMA use is restricted, retrospective clinical observations are a primary source of human data. This article reviews MDMA's behavioral pharmacology and toxicology to help clinicians recognize MDMA-related syndromes and understand serotonin's role in health and disease.

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Abstract

Abstract (±)3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”), a ring‐substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDMA produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDMA has been demonstrated in a variety of experimental animals (including non‐human primates). In monkeys, the neurotoxic dose of MDMA closely approaches that used by humans. While the possibility that MDMA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDMA use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDMA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDMA, with the hope that improved recognition of MDMA‐related syndromes will provide insight into the function of serotonin in the human brain, in health as well as disease.